Cancer is distinguished by the lack of effective immune response against the cancer. Lack of immune response can result, for example, from the fact that many tumor antigens are “self-antigens,” from lack of expression of MHC by the tumor cells and consequent lack of presentation of tumor antigens by the tumor cells, from the association of macrophages with tumors where the macrophages express cytokines that reduce immune response, and from the immunosuppressive activity of T regulatory cells (Tregs). Lack of immune response against tumors also results from the fact that tumor cells tend not to express molecules that stimulate innate immune response, that is, molecules that stimulate toll-like receptors (TLRs) or nucleotide-binding oligomerization domain (NOD)-like receptors). Cancer encompasses solid tumors as well as the hematological cancers, such as the leukemias and the myelodysplastic syndromes.
The immune system encompasses cellular immunity, humoral immunity, and complement response. Cellular immunity includes a network of cells and events involving dendritic cells, CD8+ T cells (cytotoxic T cells; cytotoxic lymphocytes), and CD4+ T cells (helper T cells). Dendritic cells (DCs) acquire polypeptide antigens, where these antigens can be acquired from outside of the DC, or biosynthesized inside of the DC by an infecting organism. The DC processes the polypeptide, resulting in peptides of about ten amino acids in length, transfers the peptides to either MHC class I or MHC class II to form a complex, and shuttles the complex to the surface of the DC. When a DC bearing a MHC class I/peptide complex contacts a CD8+ T cell, the result is activation and proliferation of the CD8+ T cell. Regarding the role of MHC class II, when a DC bearing a MHC class II/peptide complex contacts a CD4+ T cell, the outcome is activation and proliferation of the CD4+ T cell (Munz, et al. (2010) Curr. Opin. Immunol. 22:89-93; Monaco (1995) J. Leukocyte Biol. 57:543-547; Robinson, et al (2002) Immunology 105:252-262). Although dendritic cells presenting antigen to a T cell can “activate” that T cell, the activated T cell might not be capable of mounting an effective immune response. Effective immune response by the CD8+ T cell often requires prior stimulation of the DC by one or more of a number of interactions. These interactions include direct contact of a CD4+ T cell to the DC (by way of contact the CD4+ T cell's CD40 ligand to the DC's CD40 receptor), or direct contact of a TLR agonist to one of the dendritic cell's toll-like receptors (TLRs).
Humoral immunity refers to B cells and antibodies. B cells become transformed to plasma cells, and the plasma cells express and secrete antibodies. Naïve B cells are distinguished in that they do not express the marker CD27, while antigen-specific B cells do express CD27 (Perez-Andres, et al. (2010) Cytometry Part B 78B (Suppl. 1) S47-S60). The secreted antibodies can subsequently bind to tumor antigens residing on the surface of tumor cells. The result is that the infected cells or tumor cells become tagged with the antibody. With binding of the antibody to the infected cell or tumor cell, the bound antibody mediates killing of the infected cell or tumor cell, where killing is by NK cells. Although NK cells are not configured to recognize specific target antigens, in the way that T cells are configured to recognize target antigens, the ability of NK cells to bind to the constant region of antibodies, enables NK cells to specifically kill the cells that are tagged with antibodies. The NK cell's recognition of the antibodies is mediated by Fc receptor (of the NK cell) binding to the Fc portion of the antibody. This type of killing is called, antibody-dependent cell cytotoxicity (ADCC). NK cells can also kill cells independent of the mechanism of ADCC, where this killing requires expression of MHC class I to be lost or deficient in the target cell (see, e.g., Caligiuri (2008) Blood 112:461-469).
The technique of “delayed type hypersensitivity response” can be used to distinguish between immune responses that mainly involve cellular immunity or mainly involve humoral immunity. A positive signal from the delayed type hypersensitivity response indicates a cellular response (see, e.g., Roychowdhury, et al. (2005) AAPS J. E834-E846).
Autophagy is a homeostatic process by which cytosolic components and organelles are delivered to the lysosome for degradation. Autophagy is also associated with innate and adaptive immune responses to intracellular pathogens whereby cytosolic antigens are loaded onto major histocompatibility complex (MHC) class II molecules for CD4+ T-cell recognition.